Several recent studies on disruptions of the DISC1 gene in...
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Several recent studies on disruptions of the DISC1 gene in mice illustrate the great potential of genetic approaches to studying functions of putative schizophrenia susceptibility genes but also signal the complexity of the problem. An initial rationale for studying the effects of mutations in DISC1 came from the discovery of the chromosomal translocation, resulting in a breakpoint in the DISC1 gene that co-segregated with major mental illness in a Scottish family (reviewed by Porteous et al., 2006). These clinical findings were followed by a number of association studies, which reported that numerous SNPs across the gene were associated with schizophrenia and mood disorders and a variety of intermediate phenotypes, suggesting that other problems in the DISC1 gene may exist in other subjects/populations.

Recent animal models designed to mimic partial loss of DISC1 function suggested that DISC1 is necessary to support development of the cerebral cortex as its loss resulted in impaired neurite outgrowth and the spectrum of behavioral abnormalities characteristic of major mental disorders ( Kamiya et al., 2005; Koike et al., 2006; Clapcote et al., 2007; Hikida et al. 2007). Unexpectedly, however, the paper by Duan et al., 2007, is showing that DISC1 may also function as a brake and master regulator of neuronal development, and that its partial loss could lead to the opposite effects than previously described, i.e., dendritic overgrowth and accelerated synapse formation and faster maturation of newly generated neurons. In contrast to previous studies, they have used the DISC1 knockdown model achieved by RNA interference in a subpopulation of single cells of the dentate gyrus. Other emerging studies continue to reveal the highly complex nature of the DISC1 gene with multiple isoforms exhibiting different functions, perhaps depending on localization, timing, and interactions with a multitude of other genes’ products, some of which confer susceptibility to mental illness independent of DISC1. Similar molecular complexity has also emerged in other susceptibility genes for schizophrenia: GRM3 (Sartorius et al., 2006), NRG1 (Tan et al., 2007), and COMT (Tunbridge et al., 2007). With the growing knowledge about transcript complexity, it becomes increasingly clear that subtle disturbances of isoform(s) of susceptibility gene products and disruptions of intricate interactions between the susceptibility genes may account for the etiology of neuropsychiatric disorders. Research in animals will have a critical role in disentangling this web of interwoven genetic pathways.

I am very glad that our colleagues at Johns Hopkins University have published a very intriguing paper in Cell, showing a novel role for DISC1 in adult hippocampus. This is very consistent with previous publications (Miyoshi et al., 2003; Kamiya et al., 2005; and others; reviewed by Ishizuka et al., 2006), and adds a new insight into a key role for DISC1 during neurodevelopment. In short, DISC1 is a very important regulator in various phases of neurodevelopment, which is reinforced in this study. Specifically, DISC1 is crucial for regulating neuronal migration and dendritic development—for acceleration in the developing cerebral cortex, and for braking in the adult hippocampus.

There is precedence for signaling molecules playing the same role in different contexts, with the resulting molecular activity going in different directions. For example, FOXO3 (a member of the Forkhead transcription factor family) plays a role in cell survival/death in a bidirectional manner (Brunet et al., 2004). FOXO3 endows cells with resistance to oxidative stress in some contexts, and induces apoptosis in other contexts. SIRT1 (known as a key modulator of organismal lifespan) deacetylates FOXO3 and tips FOXO3-dependent responses away from apoptosis and toward stress resistance. In analogy to FOXO3,
context-dependent post-translational modifications, such as phosphorylation, may be an underlying mechanism for DISC1 to function in a bidirectional manner. Indeed, a collaborative team at Johns Hopkins, including Pletnikov's lab, Song's lab, and ours, has started exploring, in both cell and animal models, the molecular switch that makes DISC1's effects bidirectional.

Recent findings, including the interactome study by Camargo et al., 2007, and this beautiful study by Duan and colleagues, implicate DISC1 (a leading candidate schizophrenia susceptibility gene) in synaptic function, consistent with prevailing ideas of the disorder as one of the synapse and connectivity (see Stephan et al., 2006). As we learn more about DISC1 and its protein partners, evidence demonstrating the importance of microtubules in the regulation of several neuronal processes (see Eastwood et al., 2006, for review) suggests that DISC1’s interactions with microtubule associated proteins (MAPs) may underpin its pathogenic influence.

DISC1 has been shown to bind to several MAPs (e.g., MAP1A, MIPT3) and other proteins important in regulating microtubule function (see Kamiya et al., 2005; Porteous et al., 2006). As a key component of the cell cytoskeleton, microtubules are involved in many cellular processes including mitosis, motility, vesicle transport, and morphology, and their dynamics are regulated by MAPs, which modulate microtubule polymerization, stability, and arrangement. Decreased microtubule stability in mutant mice for one MAP, stable tubule only polypeptide (STOP; MAP6), results in behavioral changes relevant to schizophrenia and altered synaptic protein expression (Andrieux et al., 2002; Eastwood et al., 2006), indicating the importance of microtubules in synaptic function and suggesting that they may be a molecular mechanism contributing to the pathogenesis of schizophrenia. Likewise, DISC1 mutant mice exhibit behavioral alterations characteristic of psychiatric disorders (e.g., Clapcote et al., 2007), and altered microtubule dynamics are thought to underlie perturbations in cerebral cortex development and neurite outgrowth caused by decreased DISC1 expression or that of a schizophrenia-associated DISC1 mutation (Kamiya et al., 2005).

Our interpretation of the possible functions of DISC1 has been complicated by the unexpected findings of Duan and colleagues that DISC1 downregulation during adult hippocampal neurogenesis leads to overextended neuronal migration and accelerated dendritic outgrowth and synaptic formation. In terms of neuronal positioning, they suggest that their results indicate that DISC1 may relay positional signals to the intracellular machinery, rather than directly mediate migration. In this way, decreased DISC1 expression may result in the mispositioning of newly formed neurons rather than a simple decrease or increase in their migratory distance. Of note, MAP1B, a neuron-specific MAP important in regulating microtubule stability and the crosstalk between microtubules and actin, is required for neurons to correctly respond to netrin 1 signaling during neuronal migration and axonal guidance (Del Rio et al., 2004), and DISC1 may function similarly during migration. Reconciling differences between the effect of decreased DISC1 expression upon neurite outgrowth during neurodevelopment and adult neurogenesis is more difficult, but could be due to differences in the complement of MAPs expressed by different neuronal populations at different times. Regardless, the results of Duan and colleagues have provided additional evidence implicating DISC1 in neuronal functions thought to go awry in schizophrenia. Further characterization of DISC1’s interactions with microtubules and MAPs may lead to a better understanding of the role of DISC1 in the pathogenesis of psychiatric disorders.